Cerebral venous sinus thrombosis after COVID-19 vaccination: a case report and literature review

ABSTRACT As COVID-19 vaccines became widely available, there have been reports of neurovascular complications. In this article, we aim to report a case of cerebral venous sinus thrombosis (CVST) induced by COVID-19 vaccination, with a literature review on similar cases as well as the potential pathophysiological mechanisms. Our case is a healthy male who developed headache, vomiting, photophobia and diplopia after receiving the Ad26.COV2.S vaccine. Fundus examination showed papilledema, and magnetic resonance imaging of the brain and cerebral veins showed CVST involving the superior sagittal sinus and right transverse sinus extending into the right jugular vein. Hypercoagulability workup was unremarkable, and the patient received immunotherapy and anticoagulation. Following this treatment, symptoms resolved, and he had no residual neurologic deficits. Developing neurologic manifestations, especially severe headaches with papilledema, after COVID-19 vaccination should warrant neuroimaging. Early recognition and management of CVST are essential for good clinical outcomes.


INTRODUCTION
Several vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became available for use during the COVID-19 pandemic. The Ad26.COV2.S vaccine is a recombinant replication-incompetent human adenovirus type 26 vector encoding full-length SARS-CoV-2 spike protein in a prefusion-stabilized conformation [1]. The ChAdOx1 nCoV-19 vaccine is another adenovirus-based vaccine that consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, containing the SARS-CoV-2 structural surface glycoprotein antigen (spike protein; nCoV-19) gene [2]. Both vaccines have been shown to be safe and efficacious in protecting against COVID-19 infection and reducing the risk of critical illness [3].
The most common side effects of COVID-19 vaccination include fatigue, headache and local pain around the injection site [4]. However, there have been rare cases of cerebral venous sinus thrombosis (CVST) associated with either the Ad26.COV2.S vaccine or ChAdOx1 nCoV-19 vaccine [5,6]. CVST can present with headache or seizures and may involve elevated intracranial pressure [7]. When CVST follows a COVID-19 vaccination, it may be referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT) [8]. The proposed mechanism of VITT is similar to that of heparin-induced thrombotic thrombocytopenia (HITT) in terms of developing high levels of antibodies against the complexes of platelet factor 4 (PF4) and heparin with associated thrombocytopenia [6]. However, the immune response is triggered by the vaccine and considered to be heparin independent [8]. Medical literature discussed many VITT cases to date. Our report also offers a VITT-related CVST case in a young man with no prior history of thrombosis. We also provide a literature review on CVST associated with adenovirus vector-based vaccines, with discussion of proposed mechanisms and recent treatment guidelines.

CASE REPORT
A 28-year-old previously healthy man presented to the emergency room with severe bifrontal headaches for 2 days. The headaches were acute, throbbing and associated with blurred vision, diplopia, photophobia, nausea and vomiting, which worsened with coughing, bending forward and straining. His headaches were refractory to over-the-counter medications. He had no prior headaches. His maternal grandmother had a brain aneurysm diagnosed at the age of 50 years. He otherwise had no family history of headaches or clotting disorders. He was not on any medications but received the Ad26.COV2.S vaccine 10 days prior to symptom onset. A fundus exam revealed papilledema, and the rest of his physical and neurologic examination was otherwise unremarkable.
Magnetic resonance venography (MRV) of the brain showed filling defects within the superior sagittal sinus as well as the right transverse sinus extending into the right jugular vein (Fig. 1), thereby giving him the diagnosis of CVST. The initial laboratory workup was remarkable for platelet count 63 000/μL, international normalized ratio (INR) 1.5, partial thromboplastin time (PTT) 36.3 s and D-dimer 22 546 ng/mL. Computed tomography angiography (CTA) of the chest and abdomen showed multiple segmental and subsegmental pulmonary emboli throughout the right lung and occluded right hepatic vein with wedge-shaped hepatic segment hypodensity (Fig. 2). Venous duplex ultrasound of the bilateral lower extremities was unremarkable. An extensive workup for hypercoagulability was performed. Serum SARS-CoV-2 and PF4 antibodies were checked because of his recent COVID-19 vaccination and were positive. Along with ruling out other causes of hypercoagulability, patient's labs confirmed the suspicion for VITT. Noted that the routine COVID-19 PCR test for admission was negative.
Per the VITT protocol [9], the patient received intravenous immunoglobulins (IVIG) (1 g/kg/day) for 2 days and a continuous infusion of argatroban for 6 days, followed by oral dabigatran 150 mg two times daily. His headaches and nausea improved with supportive measures, and his diplopia soon resolved. He was discharged 2 days after being switched to oral anticoagulation. He did not have any residual neurologic deficits at the time of discharge, and normalization of platelet count was achieved prior to discharge.

DISCUSSION
CVST has to date been reported in a small number of cases after receiving the SARS-CoV2 adenoviral vector vaccines (Table 1). In these cases, the typical onset of symptoms was 1-2 weeks after vaccination. The reported clinical features included new-onset severe persistent headache, focal neurologic symptoms, visual changes and seizures [10]. In most of the cases, other clinical findings including severe abdominal pain, fever and shortness of breath have accompanied the neurological symptoms, which was indicative of systemic thrombosis [11].
Based on these reports, initial recommended investigations included complete blood count, platelet count, coagulation studies (Prothrombin time (PT), INR and PTT), D-dimer, fibrinogen and peripheral blood smear to rule out pseudo-thrombocytopenia and other causes of thrombocytopenia [12]. Other differential diagnoses to evaluate for include: DIC, sepsis, malignancy, thrombotic microangiopathy, systemic lupus erythematosus, antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria and sickle cell anemia, for which investigations were performed in our case [13]. Similar to the 4Ts score used in HITT evaluation, there has been a proposed 4Ts score for VITT evaluation to improve the diagnostic certainty [14]. The 4Ts score in VITT depends on the degree of thrombocytopenia, the timeline of symptom onset, the history of thrombosis and the presence of alternative diagnosis of thrombosis [15]. Our case had a 4Ts score of 8, which indicated a high probability of VITT.
For treating our patient, we followed the latest guidelines which recommend anticoagulation with direct oral anticoagulants (rivaroxaban, apixaban or dabigatran) or fondaparinux, and treatment with IVIG (1 g/kg/day for 2 days) [6]. Anticoagulation with heparin or warfarin should be avoided [16]. Platelet count should be monitored for recovery, and recovery itself is identified as platelet count of > 150 × 10 9 /mm 3 [17]. Even in some cases of intracranial hemorrhage, anticoagulation should be considered to prevent progressive thrombosis. Our patient tolerated the treatment with no further complications and achieved complete normalization of his platelet count and neurological symptoms.  There are a few proposed pathophysiologic mechanisms implicated in CVST development. One of these is VITT which is similar to HITT in its pathophysiology. HITT results from the formation of immune complexes consisting of autoantibodies against PF4 and heparin. These immune complexes bind to the surface of platelets and monocytes, provoking their activation by cross-linking Fc γ IIA receptors [18]. In the case of VITT, it is believed that the leakage of DNA from the adenovirus infected cells binds to PF4 and triggers the production of autoantibodies [19]. Our case tested positive for PF4 autoantibodies as in previously reported CVST cases associated with Ad26.COV2.S vaccine, which might indicate a high probability of VITT being the underlying pathophysiology of CVST in this patient. Another proposed mechanism of VITT may be independent of PF4 autoantibodies. Viral vectorbased COVID-19 vaccines contain high amounts of viral particles, which may be distributed across different body tissues including the brain. The COVID-19 adenoviral vectors might trigger an immune response in the brain, leading to localized vascular thrombosis [20]. According to the reported cases in Table 1, this mechanism could explain CVST in patients who tested negative for PF4 autoantibodies. Interestingly, those patients did not have any associated systemic thrombosis and were reported to have CVST secondary to ChAdOx1 nCoV-19 vaccine.
Despite these recent reports of COVID-19 vaccine-associated CVST, it should be noted that COVID-19 infection itself has been suggested to be a more significant risk factor for CVST. A retrospective study showed that the incidence of CVST after COVID-19 was 39.0 per million (95% CI, 25.2-60.2) compared with any 2-week period in the pre-COVID-19 [21]. There have been a few epidemiologic studies to assess the incidence of CVST during postvaccination period, which has shown conf licting evidence regarding the presence of increased incidence of CVST postvaccination. Epidemiologic studies in Europe regarding the ChAdOx1 nCoV-19 vaccine showed that the incidence of CVST has significantly increased after COVID-19, and greater than what was observed with COVID-19 mRNA vaccines and ChAdOx1 nCoV-19 vaccine [21]. However, when comparing the incidence rate between mRNA-based vaccines and vector-based vaccines, specifically ChAdOx1 nCoV-19 vaccine, the incidence rate was higher in individuals who received ChAdOx1 nCoV-19 [22]. In another epidemiologic study in the United States, there was no increased risk of CVST in the 30 days prior to COVID-19 vaccination (Pfizer-BioNTech, Moderna and Johnson & Johnson) compared with the 30 days after vaccination [23].

CONCLUSION
Although headaches may be a common side effect of COVID-19 vaccinations, a headache with increased severity should warrant further neuroimaging, and a fundus exam must be performed to assess for intracranial hypertension, a common feature of CVST. Following a thorough workup for hypercoagulability, we were able to intervene in a timely manner, which resulted in an excellent outcome with no residual symptoms or neurological deficits. Our case demonstrates the impact of early recognition of symptoms and signs of CVST in the setting of headache following COVID-19 vaccination.